Substrate Affinity and Specificity of the ScSth1p Bromodomain Are Fine-Tuned for Versatile Histone Recognition.
Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA. Electronic address: [email protected]
Department of Biochemistry & Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
Department of Biochemistry & Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: [email protected]
- Published Article
- Publication Date
Sep 03, 2019
Bromodomains recognize a wide range of acetylated lysines in histones and other nuclear proteins. Substrate specificity is critical for their biological function and arises from unique acetyl-lysine binding sites formed by variable loop regions. Here, we analyzed substrate affinity and specificity of the yeast ScSth1p bromodomain, an essential component of the "Remodels the Structure of Chromatin" complex, and found that the wild-type bromodomain preferentially recognizes H3K14ac and H4K20ac peptides. Mutagenesis studies-guided by our crystal structure determined at 2.7-Å resolution-revealed loop residues Ser1276 and Trp1338 as key determinants for such interactions. Strikingly, point mutations of each of these residues substantially increased peptide binding affinity and selectivity, respectively. Our data demonstrate that the ScSth1p bromodomain is not optimized for binding to an individual acetylation mark, but fine-tuned for interactions with several such modifications, consistent with the versatile and multivalent nature of histone recognition by reader modules such as bromodomains. Copyright © 2019 Elsevier Ltd. All rights reserved.
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The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/31327661